Synthesis and anti-HIV activity of D- and L-thietanose nucleosides

Journal of Medicinal Chemistry
Hyunah ChooChung K Chu

Abstract

Various D- and L-thietanose nucleosides were synthesized from D- and L-xylose. The four-membered thietane ring was efficiently synthesized by the cyclization of 1-thioacetyl-3-mesylate (4/38) under basic conditions. Condensation with various heterocyclic bases was conducted via Pummerer-type rearrangement to afford various nucleoside derivatives. Among the synthesized nucleosides, D-uridine (23), D-cytidine (24), D-5-fluorocytidine (25), and L-cytidine (52) analogues showed moderate anti-HIV activity, with EC50 = 6.9, 1.3, 5.8, and 14.1 microM, respectively. However, these four nucleoside analogues are cytotoxic in peripheral blood mononuclear and CEM cells. The other nucleosides are neither active nor cytotoxic. Interestingly, the oxetanocin A analogue 33 was not active. Comparison of the minimized reverse transcriptases (RTs) complexed with the corresponding triphosphates of the cytidine analogue 24 and the adenosine analogue 33 by molecular modeling studies showed that there is no difference in the binding mode of the triphosphate of the cytidine analogue 24 to the active site of HIV-1 RT from that of the triphosphate of the adenosine analogue 33. Modeling studies on the initial monophosphorylation step by deoxycytidine kina...Continue Reading

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Citations

Dec 21, 2006·Antiviral Chemistry & Chemotherapy·Chung K ChuRobert W Sidwell
Apr 1, 2017·Organic & Biomolecular Chemistry·Damien Hazelard, Philippe Compain
Jun 29, 2010·Angewandte Chemie·Laura H S SmithDavid J Procter
Jul 11, 2020·Beilstein Journal of Organic Chemistry·Jiaxi Xu
Jun 22, 2007·Journal of Medicinal Chemistry·Ugo ChiacchioGiovanni Romeo
Sep 9, 2010·Journal of Agricultural and Food Chemistry·Chia-Jui LinTsuei-Yun Fang
Sep 22, 2021·Organic & Biomolecular Chemistry·Kien P MalarneyValerie A Schmidt
Nov 20, 2021·ACS Medicinal Chemistry Letters·Derun LiChristian Fischer

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